During the treatment of certain sex steroid-dependent diseases, it is important to greatly reduce or, if possible, eliminate certain sex steroid-induced effects. For this purpose, it is desirable both to block receptor sites stimulated by sex steroids and also to reduce the amount of sex steroid available to act at these sites. For example, alternative or concurrent therapy to administration of antiestrogens could involve attempts to block the production of estrogens (e.g. by ovariectomy) such that less is available to activate receptor sites. However, prior art methods for blocking estrogen production insufficiently inhibit estrogen-induced functions. Indeed, it is possible that even in the total absence of sex steroid, some receptors may be activated. See Simard and Labrie, "Keoxifene shows pure antiestrogenic activity in pituitary gonadotrophs", Mol. Cell. Endocrinol. 39: 141-144, (1985), especially page 144.
Hence, antagonists of sex steroids may produce greater therapeutic results than therapy which only inhibits sex steroid production. Prior art antagonists, however, often have insufficient affinity for receptors, and some, although capable of binding the receptors, may themselves act as agonists and undesirably activate the very receptors they are intended to shield from activation. There is, therefore, a need in the art for antiestrogens which effectively block estrogen receptors with minimal or no agonistic effect. The net effectiveness of a compound is affected by both its agonistic (undesirable) and antagonistic (desirable) activities. In Wakeling and Bowler, "Steroidal Pure Antioestrogens", J. Endocrinol. 112: R7-R10 (1987), certain steroid derivatives are said to act as an antiestrogens.
In U.S. Pat. No. 4,094,994, it is disclosed that the use of certain antiestrogens may inhibit certain human breast tumor cells.
H. Mouridsen et al., Cancer Treatm. Rev. 5: 131-141 (1978), discloses that Tamoxifen, an antiestrogen, is effective in remission of advanced breast cancer in about 30 percent of the women patients treated.
The combined use of the antiestrogen Tamoxifen and a luteinizing hormone-releasing hormone agonist, Buserelin, is also known for treatment of breast cancer. See, for instance, Klijn et al. J. Steroid Biochem. 420: no. 6B, 1381 (1984). The objective remission of such cancers, however, remains unacceptably low.
It has been found that certain 7.alpha.a-substituted derivatives of estradiol, for example a 7.alpha.--(CH.sub.2).sub.10 CONMeBu substitution, possess antiestrogenic activity (Bowler et al., 1985; Eur. Patent Application 0138504; Wakeling and Bowler, J. Steroid Biochem. 30: 141-147 (1988). See also U.S. Pat. No. 4,659,516. The substitution (CH.sub.2).sub.9 SOC.sub.5 H.sub.6 F.sub.5 has also been used (Wakeling et al., Cancer Res. 51: 3867-3873, 1991).
Certain --(CH.sub.2).sub.10 CONMeBu substituted compounds are also disclused in U.S. Pat. No. 4,732,912 (See e.g. example 5 and 16). See also EP Pat. No. 166 509, EP Pat No. 124 369, EP Pat. No. 160 508, EP Pat. No. 163 416, U.S. Pat. No. 4,760,061, U.S. Pat. No. 4,751,240 and Wakeling A. E. and Bowler, J., J. Endocrinol. 112: R7-R10 (1987).
Von Angerer et al. discuss other antiestrogens in "1-(aminoalkyl)-2-phenylindoles as Novel Pure Estrogen Antagonists", J. Med. Chem. 1990; 33: 2635-2640. In U.S. Pat. No. 4,094,994, where it is said that the use of certain antiestrogens inhibit certain human breast tumor cells. See also DE 3821148.
A. Saeed et al., J. Med. Chem. 33: 3210-3216, 1990; A. P. Sharma et al., J. Med. Chem. 33: 3216-3222 and 3222-3229 (1990) described the synthesis and biological activities of certain 2,3-diaryl-2H-1-benzopyran analogs having the following molecular structure: ##STR1## for use as antiestrogens. In N. Durani et al., J. Med. Chem. 32: 1700-1707 (1989), the synthesis and biological activities of benzofuran and triarylfuran analogues as antiestrogens are described.
In applicant's grandparent priority application hereto, an international version of which is now published as WO 93/10741, a class of improved estrogen activity inhibitors is disclosed, including the inhibitor EM-343, i.e. 7-hydroxy-3-(4'-hydroxyphenyl)-4-methyl-2-(4"-(2'"-piperidinoethoxy)phenyl -2H-benzopyran and its prodrugs. The present invention relates in part to particular types of benzopyran antiestrogens and to certain modified benzopyran antiestrogens, all of which provide further improved characteristics. It has now been found that certain prodrugs of EM-343 provide advantages that are especially efficacious. EM-343 may exert as either of two enantiomers or as a mixture of the two. It has now been discovered that one of the two enantiomers is more effective than the other. That more effective enantiomer and prodrugs thereof are also the subject of the present invention.
Derivatives of active drugs which are, by in vivo enzymatic or spontaneous reactions, transformed into the active drugs are known (see H. Bundgaard, Design and Application of Prodrugs. In A textbook of Drug Design and Development; Edited by P. Krogsgaard-Larsen and H. Bundgaard; Harwood Academic Publishers GmfH, Chur, Switzerland, 1991, pp. 113-191). In the steroid series, for example, Druzgala et al. (J. Steroid Biochem. Molec. Biol. 38, 149-154, 1991) have described prodrugs of glucocorticoids. Bodor et al. in U.S. patent application No. 4,213,978 and in German Patent Application Publication No DE 29 48 733 disclose the use of thiazolidine derivatives of progesterone as topical drugs. Percutaneous absorption of prodrug derivatives of estrogens and progestins are reported by Friend DR in Critical Reviews in Therapeutic Drug Carrier Systems, vol. 7 (2), pp. 149-186, 1990.